Given the heterogeneity of breast cancer and the range of sensitivity to different therapies, successful management of cancer necessitates personalized therapy (Loo et al., (2011) J. Clin. Oncol. 29: 660-666; Ouerol & Bogdanov (2008) Handbook Exp. Pharmacol. 37-57 (2008). This entails both optimizing therapy to treat each individual patient and monitoring the response to therapy in near real time. Early response monitoring would allow effective treatments to be continued, and for the cessation of ineffective treatments prior to significant disease progression. However, the ability to accurately determine tumor response to therapy on a short time scale (e.g. within a day) has yet to be achieved, even though it is widely accepted that therapeutic-response monitoring at early stages is crucial for effective cancer treatment.
One predominant subcellular response associated with both radiation therapy and the most common chemotherapeutic agents applied to cancers is severe DNA damage. This severe DNA damage is sensed by the enzyme poly(ADP ribose) polymerase-1 (PARP-1), the activity of which becomes significantly elevated in cancer upon positive response to chemo and radiation therapy. In addition, it has been shown that some cancers have increased PARP-1 basal activity levels that may be responsible for a portion of the resistance of these cancers to certain conventional chemotherapeutic agents (Ganesan S. (2011) Sci. Signal 4: pe15). Therefore, PARP-1 sensitive probes could have two-fold utility: (1) a criterion for cancer therapy individualization, and (2) a biochemical marker of early therapeutic response.
Current clinical methods of monitoring therapeutic efficacy involve measures of tumor size either through palpation, ultrasound, MRI, or mammography. However, all of these techniques are limited by poor accuracy and reproducibility, false results, poor correlation with histopathological response, and the inability to detect therapeutic response earlier than after two rounds of therapy, or at least weeks after treatment initiation (Loo et al., (2011) J. Clin. Oncol. 29: 660-666; Aboagye E. O. (2010) Br. J. Radiol. 83: 814-822; Choi et al., (2010) J. Surg. Oncol. 102: 392-397; Dent & Bristow (2011) J. Clin. Oncol. 29: 2130-2132; Heldahl et al., (2011) J. Magn. Reson. Imaging 34: 547-556; Sharma et al., (2011) NMR Biomed. 24: 700-711).
Weissleder et al. reported an inhibitor-based molecular probe for PARP-1, but they bind PARP-1 independent of enzyme activity and only report on the amount of enzyme present in the cell (Keliher et al., (2011) Chem. Med. Chem. 6: 424-427; Reiner et al., (2011) Angew Chem. Int. Ed. Engl. 50: 1922-1925; Ullal et al., (2011) ACS Nano. 5: 9216-9224). These probes therefore cannot differentiate active from inactive PARP-1.